Early- and delayed antipsychotic response and prediction of outcome in 528 severely impaired patients with schizophrenia treated with amisulpride.

INTRODUCTION: 'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various antipsychotics. METHODS: Response and remission rates were assessed in 528 severely ill patients with schizophrenia at baseline, week 2, 4 and 12 using PANSS, SWN-K, CGI-S, and SOFAS. The clinical measures were combined to one outcome criterion (CombOut). Predicitive validity was analyzed for CombOut using linear regression models. RESULTS: Rate and time to response differed markedly between outcome measures. 32% reached positive symptom response at week 2, 58% at week 4 and 85% at week 12. Non-response at week 4, but not at week 2 was predictive for later non-response. The combined outcome criterion was best predicted by early response in subjective wellbeing (T=-7.88, p<0.001) and social functioning (T=-7.43, p<0.001). DISCUSSION: Rate and time to response might depend on sample characteristics and outcome measure. In severely ill patients early antipsychotic response is possibly delayed from the first 2 to the first 4 weeks. Early response in subjective wellbeing and social functioning are strong predictors for overall outcome, which make them a useful supplementation to the assessment of symptomatic response.

Amisulpride doses and plasma levels in different age groups of patients with schizophrenia or schizoaffective disorder.

Because of a unique pharmacodynamic profile, amisulpride seems appropriate for treatment of elderly patients with schizophrenia. In a large-scale naturalistic therapeutic drug monitoring study, daily amisulpride dose, trough and dose-corrected amisulpride plasma levels, co-medication, clinical effectiveness (CGI) and side effects (UKU) were compared between age groups in 395 patients with schizophrenia or schizoaffective disorder (46% women; mean age 39.1 +/- 14.2 years, range 18-83 years) under amisulpride therapy. Mean amisulpride doses (574 +/- 269 mg/day), plasma levels (304 +/- 274 ng/mL), dose-corrected amisulpride plasma levels (C/D ratios, 0.52 +/- 0.41 ng/mL:mg), clinical response (at least moderate improvement, 71.6%), and side effects (any side effect, 32.2%; extrapyramidal symptoms, 14.9%) were comparable between age groups (P > 0.25). At higher age, significantly more benzodiazepines (P = 0.04), non-benzodiazepine hypnotics (P = 0.004) and non-psychotropic medications (P < 0.0001) were prescribed. The naturalistic study showed higher C/D ratios in women (P = 0.019) and a slight increase of C/D ratios with age (P = 0.026), but no substantial age-dependent effects on amisulpride doses or plasma levels. In patients above 60 years, clinical response was associated with lower amisulpride plasma levels (P = 0.016) at comparable doses. Neither the age-dependent decrease of amisulpride clearance nor the significantly higher prevalence of co-morbidity and co-medication seem to be the reasons for definite clinical concerns against amisulpride treatment of elderly if contraindications are seriously taken.

A pilot study of the safety and efficacy of amisulpride and risperidone in elderly psychotic patients.

OBJECTIVE: The primary objective of this randomised, active-controlled, parallel group, double-blind study was to evaluate the tolerability of treatment with either amisulpride or risperidone in elderly patients with schizophrenia aged over 65 years; evaluation of efficacy was a secondary objective. METHODS: The study included patients of either sex aged 65 years or older fulfilling DSM IV-diagnostic criteria for psychotic disorders and who presented psychotic symptoms severe enough to require antipsychotic medication. Subjects were randomly allocated to a flexible dose of either amisulpride (100-400mg/day) or risperidone (1-4 mg/day) for six weeks following a three- to six-day placebo wash-out period. Safety assessment involved adverse event reporting, physical examination, blood pressure, heart rate and ECG monitoring, and laboratory tests. Extrapyramidal symptoms were evaluated with the Simpson-Angus Scale, Barnes Akathisia Scale and the AIMS. Efficacy parameters were changes in score on the PANSS, BPRS, CDS and MMSE scores. RESULTS: Thirty-eight patients were randomised, 25 to amisulpride and 13 to risperidone. A total of 26 adverse events were experienced by 10 patients in the amisulpride group and five patients in the risperidone group. One patient in each group discontinued the study due to the emergence of a movement disorder. Changes in scores on the three measures of extrapyramidal symptoms were similar in the two groups. The PANSS total score decreased by 27.8% in the amisulpride group and by 29% in the risperidone group between inclusion and study end. CONCLUSION: Amisulpride and risperidone are generally well tolerated in elderly patients with schizophrenia. Both drugs appeared to be efficacious in this study population, with no differences in efficacy being observed. However, the sample size was too low to reveal potential inter-group differences. Both these atypical antipsychotics thus appear to be suitable for the treatment of schizophrenia in the elderly.

Remission of severely impaired subjective wellbeing in 727 patients with schizophrenia treated with amisulpride.

UNLABELLED: Studies of subjective wellbeing (SW) in schizophrenia have missed to define and to assess rate and predictors of SW response (SW-res) and SW remission (SW-rem). METHOD: A total of 727 patients with schizophrenia and severely impaired SW at entry (Subjective Wellbeing under Neuroleptics Scale, short version, SWN-K, total score < or =60) were treated with amisulpride over 12 weeks. SW-res was defined as SWN total score increase of at least 20% and by at least 10 points and SW-rem as total score of > or =80 points. RESULTS: Seventy percent fulfilled the SW-res criterion at week 4. At week 4 and week 12 (endpoint), the SW response criterion distinguished between patients with or without later SW remission and overall symptomatic and functional response. While 39% fulfilled the SW-rem criterion at endpoint, only 9.1% without early SW-res were in SW-rem at follow-up. Regression analyses indicated that SW-res was mainly predicted by greater severity of positive symptoms at baseline and SW-rem by lower severity of negative symptoms and better social functioning, and particularly by early SW-res. CONCLUSION: Patients with a risk of SW non-remission need to be identified early with subsequent treatment adaptation according to recommendations for incomplete remission and treatment resistance in schizophrenia.

Gender aspects in the clinical treatment of schizophrenic inpatients with amisulpride: a therapeutic drug monitoring study.

INTRODUCTION: It is assumed that female and male schizophrenic patients respond differentially to acute and chronic treatment with antipsychotics because of pharmacokinetic and pharmacodynamic factors linked to hormonal and constitutional gender differences. However, to date no empirical evidence exists in support of this notion. METHODS: In a naturalistic clinical study, we investigated gender differences in a sample of schizophrenic inpatients with acute exacerbation treated with the atypical antipsychotic amisulpride, a selective dopamine D2/D3 receptor antagonist with proven antipsychotic efficacy. Prescribed amisulpride dose, plasma level, clinical response (CGI), and side effects (UKU) were assessed in 99 patients (62 % male, age 18-66 years) under antipsychotic monotherapy with amisulpride at daily doses > or = 400 mg. RESULTS: Female patients were significantly older (38.5 +/- 11.8 years) than male patients (32.3 +/- 10.9 years; P = 0.01). Prescribed amisulpride doses were comparable for men (673 +/- 216 mg) and women (665 +/- 229 mg). However, dose-corrected steady-state amisulpride plasma levels (men 0.41 +/- 0.31 ng/mL/mg; women 0.60 +/- 0.39 ng/mL/mg; P = 0.007) were significantly higher in female patients even after age adjustment. No significant differences between men and women emerged with respect to clinical response (77 % vs. 79 %, respectively) and the occurrence of any side effect (41 % vs. 37 %, respectively). DISCUSSION: Except for higher dose-related plasma amisulpride levels in women, the explorative study unveiled no clinically relevant gender-specific aspects regarding prescribed dose, effectiveness, and side effects.

Competence to give informed consent to clinical studies. Statement by the taskforce on "ethical and legal questions" of the Association for Neuropsychopharmacology and Pharmacopsychiatry ("Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie [AGNP]").

Over the last 50 years, patient autonomy has become an increasingly important part of the principles of medical ethics, or rather of the ethics of the doctor-patient relationship. While the principle of charity and the associated paternalism became less important, the patient's active consent became more and more relevant (Sass, 1989; Bayer, 1998; Nedopil, 1998). This development was inevitably also accompanied by a demand for more detailed information prior to medical interventions (Appelbaum and Grisso, 1988; Weisstub, 1990; Kreussler, 1997; Ulsenheimer, 1995; Laufs, 1997; Sommer, 1997) and for complete information on medical procedures subsequent to interventions (e. g. Bender, 1997). Determination of a person's competence to give informed consent is a central problem in the assessment of his expression of consent to a medical intervention. The capacity to adequately express consent can be impaired at certain stages of life and during some illnesses. Patients in borderline situations, children, mentally ill patients and old people with dementia may either be limited in their capacity to give informed consent, or be completely unable to do so. This results in special ethical problems when such groups are included in research projects.

Negative symptoms in schizophrenia: considerations for clinical trials. Working group on negative symptoms in schizophrenia.

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.

Pilot controlled double-blind study of the hypnotic effects of zolpidem in patients with chronic 'learned' insomnia: psychometric and polysomnographic evaluation.

In a pilot double-blind trial in 21 patients with learned or idiopathic insomnia (DSM-IIIR), patients received placebo for 1 week (nights 1-7), either active (zolpidem, 10 mg) or placebo treatment for 2 weeks (nights 8-21) and then placebo for a further week (nights 22-28). Variables to measure efficacy, rebound and withdrawal were assessed daily from day 1 to day 28. Polysomnographic recordings together with sleep cycle analysis were performed on nights 7, 21 and 28. Patients treated with 10 mg zolpidem for 2 weeks had significantly improved sleep efficiency at the end of the randomised double-blind phase compared with the placebo group. Fractionated sleep-cycle analysis showed an increase in slow-wave sleep during the first 2-hour cycle after sleep onset. During the withdrawal placebo week, most of the main sleep variables remained relatively stable in the zolpidem group (nights 22-28), and deteriorated further in the placebo group. At the end of the withdrawal phase, there was a statistically significant difference between groups, in favour of the zolpidem treatment, in sleep efficiency, total sleep time, absolute and percentage of time awake, and percentage of REM sleep. REM sleep, which was normal in both groups at baseline, decreased significantly in the placebo group between nights 22 and 28 (during the withdrawal placebo week) compared with the zolpidem treatment group, and the number of periods of time awake increased. Minor subjective complaints were recorded under zolpidem and were comparable with those under placebo. Zolpidem seemed to improve some important sleep variables, when assessed both objectively and subjectively. The sleep cycle analysis suggested a possible shift of slow-wave sleep to an earlier period of the night, with a more physiological sleep structure. There was no evidence for withdrawal or rebound after stopping the 2 weeks of zolpidem treatment, but rather signs that the effect of zolpidem outlasted active treatment. The present pilot study justifies a prospective confirmatory comparison of zolpidem with benzodiazepines in an adequate number of patients and withdrawal after 6-8 weeks of treatment.

Long-term polysomnographic study of the efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia.

The effects of 20 mg zolipidem were studied in an open, polysomnographically-monitored 179 day trial in 14 elderly psychiatric patients suffering from severe insomnia. After a placebo run-in of 7 days, zolpidem was given for 179 days followed by a 30-day wash-out period. Polysomnographic recordings (PSG) were performed just before active treatment; 30, 90 and 179 days into the treatment period; and at the end of the wash-out period. Statistically significant improvements in total sleep time, sleep efficiency and percentage of rapid eye movement sleep were observed after 30 days, all of which were maintained at 179 days. Sleep stages 1-4 all changed, with a significant decrease in percentage of stage 1, and a significant increase in both percentages of stage 2 and 3, and duration of stages 3 and 4 at the end of active treatment. After a 90-day follow-up period, only stage 3 sleep and sleep efficiency were no longer significantly changed compared to baseline, all other criteria showing maintenance of efficacy. Slow-wave sleep, which was increased during active treatment, decreased in the follow-up period. No serious adverse events were observed. These results suggest that, contrary to other hypnotics, zolpidem, after long-term administration, improves objective sleep parameters and may normalize a disturbed sleep architecture.

Effects of single doses of alpidem, lorazepam, and placebo on memory and attention in healthy young and elderly volunteers.

The aim of the present study was to compare the effects of alpidem, a new imidazopyridine derivative with benzodiazepine-like anxiolytic effects, with those of lorazepam and placebo on memory and attention in two age groups of healthy volunteers. The study design was that of a randomized double-blind crossover trial with 12 young (18-30 years old) and 12 elderly (65-80) subjects. At weekly intervals, each subject was administered single oral doses of 25 mg alpidem, 50 mg alpidem, 1 mg lorazepam, and placebo in a randomized sequence. Computerized memory and attention tests were performed 90 minutes before and 320 minutes after drug administration. Lorazepam and alpidem 50 mg produced memory impairments: for verbal memory tests the difference against placebo was highly significant for both drugs, while for visual memory this impairment was significant for lorazepam only. No memory effects were seen with 25 mg alpidem. There were no significant drug effects on attention, suggesting a specific amnestic effect not explained by general sedation. Performance of the elderly subjects was much lower than that of the younger ones in both memory and attention tasks. It was not possible to observe any interaction effects between drug and age.

Psychomotor disturbances in psychiatric patients as a possible basis for new attempts at differential diagnosis and therapy. II. Cross validation study on schizophrenic patients: persistence of a "psychotic motor syndrome" as possible evidence of an independent biological marker syndrome for schizophrenia.

This study investigates the existence and course of psychomotor symptoms in schizophrenic patients (n = 57, both treated and untreated with antipsychotic drugs) as compared to 25 healthy controls. Previous psychometric studies had suggested the existence of a "psychotic motor syndrome" (PMS) both in (untreated) schizophrenic and endogenous depressed patients, consisting of disturbances of lip and tongue movements, fine and gross movements of the dominant right hand and impaired complex motor coordination of the extremities. We confirmed the existence of the PMS in this study. There was no correlation of the PMS with the psychopathological status of the patients, or with extrapyramidal side-effects of the drugs used, perhaps indicating an independent "basic syndrome" ("Basisstörung"). Factorial analyses revealed similar structures both in schizophrenic and healthy persons; the differences in motor performance may be due to an impairment of the first factor "general motor ability" in schizophrenic patients. The PMS did not disappear parallel to the psychopathological improvement of the patients, nor in the symptom-free remission interval. The role of the PMS as possible independent biological marker syndrome for schizophrenia can consequently be further supported, with its implications towards the differential diagnostic and therapeutical values of this syndrome.